Intracellular calcium is an important factor causing a large variety of physiological responses such as neuronal excitement, muscle contraction, hormone secretion, fertilization, immune response, cell motility, and cell death; and the concentration is regulated by means of ion channels or pumps, such as voltage-dependent calcium channels and receptor-operated calcium channels. The voltage-dependent calcium channels are calcium channels which are opened and closed depending on the change of the potential difference between inside and outside of the cell, and exist on the cellular membrane of muscles or nerve cells. The voltage-dependent calcium channels are currently classified into L-type, T-type, N-type, P/Q-type, and R-type calcium channels, based on electrophysiological characteristics and pharmacological characteristics. Unlike L-type, N-type, P/Q-type and R-type calcium channels, which are classified as medium potential and high potential activated calcium channels in view of the voltage activation threshold, T-type calcium channels are activated at a potential that is close to the resting membrane potential. Therefore, the T-type calcium channels is believed to play a role as triggers for influx of calcium into the cell, and to participate in the pacemaker activity, production of low-threshold calcium spikes, and burst firing.
T-type calcium channels include three subtypes such as Cav3.1 (α1G), Cav3.2 (α1H) and Cav3.3 (α1I); and expression of the channel in, for example, the brain, nerve tissues, heart, kidneys, liver, pancreas, smooth muscles, testicles has been reported. It has been suggested that activation of the T-type calcium channels in these organs and tissue cells described above may cause intracellular calcium overload, and may participate in the onset and progress of various pathological conditions such as, for example, hypertension, tachyarrhythmia including atrial fibrillation, cardiac hypertrophy, cardiac failure, renal dysfunction, and cancers. Therefore, T-type calcium channel antagonistic drugs are believed to be effective in the treatment or prevention of these diseases (Non-Patent Documents 1 to 5).
One of known T-type calcium channel antagonistic drugs is mibefradil, however, this drug is not commercially available at present due to problems such as drug interaction. Furthermore, for example, Patent Document 1 discloses a 3,4-dihydroquinazoline derivative; Patent Document 2 discloses a quinazoline derivative; Patent Document 3 discloses a pyridylamide derivative; Patent Documents 4 and 5 disclose 3-fluoropiperidine derivatives; Patent Document 6 discloses an indole derivative; Patent Document 7 discloses an oxadiazole derivative; Patent Documents 8 and 9 disclose thiazole derivatives; Patent Document 10 discloses an isoxazole derivative; and Patent Document 11 discloses a 1,3-dioxoindole derivative, as the T-type calcium channel antagonistic drugs. However, these compounds have not been hitherto put to clinical use.